Several publications and patent documents are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications and documents is incorporated by reference herein.
Techniques in bioconjugate chemistry have provided effective tools for endowing biomolecules with novel properties. Conjugation reactions are routinely employed to modify proteins and nucleic acids so as to incorporate fluorophores, ligands, chelates, radioisotopes, affinity tags, and numerous other groups therein (G. T. Hermanson, Bioconjugate Techniques, Academic Press: San Diego, Calif., 1996). When performed on solid phase support, these reactions can be used to modify synthetic oligonucleotides and polypeptides with exceptional efficiency (reviewed in Virta et al., Tetrahedron, 2003, 59, 5137). In many cases, solid-phase conjugation reactions can be adapted for automated protocols, allowing the development of novel combinatorial libraries and microarray applications.
Polypeptides, while capable of exhibiting an extraordinary range of bioactivities, often display poor pharmacological properties. For this reason, synthetic mimics of peptides have been the focus of vigorous development by medicinal and bioorganic chemists. A variety of oligomeric peptidomimetics have been introduced that show potential as partial mimics of natural polypeptide species in that they exhibit some of the structural and functional attributes of natural polypeptides (Patch et al., Curr. Opin. Chem. Biol., 2002, 6, 872). Further elaboration of peptidomimetic structures may lead to a greater range of capabilities for this promising class of molecules.
N-substituted glycine oligomers (α-peptoids) and N-substituted β-alanine oligomers (β-peptoids) are examples of a promising class of peptidomimetics. Peptoids are oligomers based on a peptide backbone, which can be produced by an efficient, automated solid-phase synthesis that facilitates the incorporation of diverse N-pendant sidechains in a sequence-specific manner. As such, peptoids are a class of non-natural, sequence-specific polymers that represent an alternative derivative of a peptide backbone, the sequence and length of which can be precisely controlled. Structurally, peptoids differ from polypeptides in that their sidechains are pendant groups of the amide nitrogen rather than the α-carbon (Simon et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 9367; Zuckermann et al., J. Am. Chem. Soc., 1992, 114, 10646). Peptoids are particularly useful for biomedical applications because these molecules are largely invulnerable to protease degradation and hence are more stable than polypeptides in vivo. Peptoids have also been shown to be more cell permeable than their peptide analogues (Kwon et al. J. Am. Chem. Soc., 2007, 129, 1508). These properties enhance bioavailability. Moreover, peptoids, which are synthetically produced by definition, can be produced essentially in the absence of impurities.
Polyvalency is a powerful method utilized by nature to enhance the binding strength of bioactive ligands. Polyvalency exerts its affect by means of the display of multiple copies of one or more chemical groups. Although these groups may possess only modest binding strengths in isolation, as part of a larger complex the binding interactions can sum to provide a very strong interaction. A variety of approaches have been developed by chemists to mimic polyvalent display on polymers or dendrimers. Typically, these products exhibit limitations resulting from the difficulty of synthesis and/or the polydispersity of the scaffold. Ideally, chemists would seek to display ligands in a precise fashion in which the spacing between one or more of the conjugated groups can be controlled. Thus, there is a need for novel methods that can be used to perform multi-site chemical conjugation onto an oligomer or polymer scaffold.